TLR-dependent formation of multinucleated giant cells

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In mycobacterial infections multinucleated giant cells (MGCs) arise from macrophages in a tightly regulated process, which is confined, to multicellular granulomas. In the first three years of funding we have delineated that Toll-like receptor 2 activation instructs polyploid MGC via induction of replication stress and a DNA damage response leading to modified cell divisions and mitotic defects. An important intermediate in this process is nitric oxide, which causes DNA damage and impairs p53 function. Thus mycobacteria appear to paradoxically profit from antimicrobial efforts by driving transformation into permissive MGCs. In the upcoming three years we aim at further defining differentiation mechanisms underlying MGC formation, since they form rational therapeutic targets. Our central hypothesis is that common monocyte progenitors (cMoPs) are dedicated MGC precursors. Concomitant to bone-marrow egress and recruitment to the site of infection, cMoPs acquire a novel phenotype with expression of typical monocyte surface markers, yet preservation of proliferative capacity and MGC precursor potential. Moreover, we propose that the myeloid transcription factor IRF8 is essential for full antimicrobial MGC function. The specific aims are a) to define the transcriptional program in the formation and function of MGC originating from cMoPs, b) to define the qualitative role of IRF8 in the development of tissue macrophages, and c) to analyze immunometabolism in MGC. Deciphering the cellular and transcriptional preconditions for MGC formation, with lack of IRF8 as a model immunodeficiency for mycobacterial infections, is expected to reveal novel strategies to boost antimycobacterial immunity.